Project Summary/Abstract Anxiety disorders have a higher prevalence rate in women when compared to men. This is particularly so for post traumatic stress disorder (PTSD); an anxiety disorder that stems from fear memory persistence induced by traumatic stress exposure. Women are twice as likely to suffer from PTSD as men and more likely to suffer from chronic PTSD (symptoms experienced greater than a year) than men. Ovarian hormones, and specifically estrogen levels, have been implicated in enhanced susceptibility to traumatic stress in women. However, this contrasts with human experiments that have demonstrated high estrogen levels inhibit anxiety and rodent stress models that have shown stress exposure that leads to persistent fear memory expression in males does not have this same effect in females. How can estrogen levels simultaneously be a risk factor for developing anxiety disorders after trauma and protect against high levels of anxiety and persistent fear memory expression induced by stress? Estrogen binds to estrogen receptors (ERs), which results in the translocation of ERs to the nucleus of cells where they exert genomic effects that can last for hours - days. These ER-induced genomic effects could be critical for the protective effects of estrogen. The menstrual cycle in women lasts 21 - 45 days with a period of 5-7 days where estrogen levels are chronically low. Female rodents have an estrous cycle that last 4-5 days with a considerably shorter period of low estrogen levels. As a result, ER activation (via genomic mechanism) may never decrease in female rats, because estrogen levels are low for a short period of time. In women, estrogen levels are low for a longer period of time, which means that ER-induced activation may become chronically decreased, and this period of decreased ER effect may represent a stress-susceptibility period. Thus, high levels of circulating estrogens may endow stress resilience, but stress susceptibility may follow when estrogen levels go from high to chronically low in naturally cycling females. To test this hypothesis, we will first show that chronically antagonizing ERs in female rats with an estrous cycle will make them more susceptible to the effects of stress on persistent fear memory (specific aim #1). Next, we will show that chronic antagonism of ERs within critical nodes of the fear circuit will make female rats with an estrous cycle more susceptible to the effects of stress on persistent fear memory (specific aim #2). Lastly, we will use fMRI in awake rats to show that chronic ER antagonism in female rats with an estrous cycle will make them more susceptible to the effects of stress-induced changes in brain volume and functional connectivity within the fear circuit. This research proposal will help explain how cycling estrogen levels can simultaneously lead to stress susceptibility, and is relevant to explaining why female humans have such a higher risk for developing stress- induced anxiety disorders.